N-(4,4-diloweralkyloxy and thio butyl) benzene sulfonamides



United States Patent ice $2,225

i R is selected from the group consisting of alkyl, halogen, i 3 501 512nitro, amino and ac lamino;

N'(4,4'DILOWERALK&LO,XY AND THIO BUTYL) Y is selected from the groupconsisting of oxygen and sul- BENZENE SULF0NASMI:)ESC B n Phl] and PeterUpper Darby and tan ey e R is selected from the ron consistin of alk lrovided del hia Pa. assignors to American Home Products Corg p y poratioil, New York, N.Y., a corporation of Delaware that 3 13 than ylalkylaminoalkyl, alkoxy- N0 Drawing. Original application Jan. 21,1966, Ser. No. alkyl m 9 3 Phenyl, P lf y y halO- 536,479, now PatentNo. 3,453,289, dated July 1, 1969. alkylphenyl; e y y ny y a y n Dividedand this application Feb. 3, 1969, Ser. No. a secondp-substituted-phenylsulfonyl pyrrolidme group 816,437 10 of the similargeneral formula:

Int. Cl. C07c 143/78 Bl US. Cl. 260397.7 3 Claims I v I This is adivision of application Ser. No. 536,479, filed Ra N SQ 2 Jan. 21, 1966,now Patent No. 3,453,289, dated July 1, 1969. R R

This invention relates generally to 2-substituted l-arylsulfonylpyrrolidine compounds and to starting materials wherein, however, R isspecifically alkyl, but R R R for preparing the former, and, moreparticularly, to novel R R and Y are. each as defined above.

p-substituted-phenylsulfonyl pyrrolidine derivatives hav- Thep-substituted-phenylsulfonamide derivatives of the ing pharmacologicalactivity, and to valuable intermediinvention which are particularlyuseful as intermediates in ates for preparing said novel derivatives.the preparation of the compounds of Formula A above The novelpharmacologically active. p-substituted-phenare those having thefollowing general formula:

ylsulfonyl pyrrolidine derivatives encompassed by the (B) presentinvention are those having the following general 1 1 formula: l l

R (A) RQ-SOT-NHwHmOmOROQ I l R4 I i Q YRfl wherein R R R R and R are asdefined for the compounds of Formula A above; and I R is alkyl. Iwherein R and R are each selected from the group con- The generalsyntheses of the compounds of Formulae sisting of hydrogen, alkyl,halogen, nitro and acylamino; A and B above are representedschematically below Where- R and R are each selected from the groupconsisting of in R R R R R R and R have the same meanings hydrogen,alkyl, halogen, nitro, amino and acylamino; as in said formulae:

R2 R1 R2 R1 l l I B SO2CHH2N(CH2) CH(0H )z R SOZNH(CHQ)3CH(OR7)Z R?-S02'I I'-0-R b R2 R1 R1 R2 I l I HOCH2CH2OH a I v v RJ- SOz-N OCHeCHzONSO2 -R3 R R1 v v I I I I I 1 1': k/ U I l E i v 1 (V) R3SO2NH(CH2)aCH(OR )z I R2 R: R4 R5 H+ I I In HSCHzOH2N(C2H )z R3 v SO2-NSCHZCH2N O2H5 2 v F R R v v 1,.v .R R p Hs S' l v p a a U R SOzN Sig-s ii I I U R5 I U In preparing the compounds'of theinvention,aphenylsulfonyl chloride (1) in an inert solvent such asdimethoxyethane is added to a cold solution of an amino-acetal (II). Thereaction solution is stirred, benzene is added and the mixture is thenextracted with water. The organic layer is dried and the solvent isremoved under reduced pressure to give the benzenesulfonamide denoted byFormula III. Treatment of this compound in alcohol with mineral acidcauses ring closure to form the pyrrolidine (IV).

The bis compounds denoted by Formula V are pr pared by dissolving thesulfonaniide compounds of Formula III in ethylene glycol (or ethylenedithiol when the thio analogsare desired) containinga trace of a mineralacid such as hydrochloric acid and heating to around 50 to 80 C. Theresulting product precipitates upon standing overnight and can berecrystallized from benzene.

Treatment of compounds of Formula III with a mercapto-tertiary amine inthe presence of a mineral acid yields the 2-dialkylaminoalkylthiocompounds of Formula VI. Similarly, treatment of said compounds ofFormula III with a thiophenol yields the correspondingZ-phenylthiopyrrolidine compounds. In like manner, treatment ofcompounds of Formula III in acid medium with a m reapto-thiazine givesthe corresponding Z-thiazinylthiopyrrolidine compounds (VII).

It has been discovered that compounds of Formula A meeting the describedqualifications, have useful pharmacological properties. Morespecifically, said compounds have been found to exhibit utility ascentral nervous system, diuretic and antiviral agents.

When the compounds of Formula A are employed for their central nervoussystems, diuretic and antiviral activity in mammals, they may beadministered alone or in combination with pharmaceutically acceptablecarriers, the proportion of which is determined by the solubility andchemical nature of the compound, chosen route of administration andstandard pharmaceutical practice. For example, they may be administeredorally in the form of tablets or capsules containing conventionalexcipients, or in the form of solutions; or they may be injectedparenterally, that is intramuscularly, intravenously or subcutaneously.For parenteral administration they may be used in the form of sterilesolutions containing other solutes, for example, enough saline orglucose to make the solutions isotonic.

The dosage of the present therapeutic agents will vary with the form ofadministration and the particular compound chosen. It will generally befound that when the composition is administered orally, largerquantities of the active agent will be required to produce the sameeffect as a smaller quantity given parenterally. In general, thecompounds of this invention are most desirably administered at aconcentration level that will generally afford effective results withoutcausing any harmful or deleterious side effects and preferably at alevel that is in the range of from about 0.1 mg. to about 7 mg. per kg.of body weight per day, although as aforementioned variations willoccur. However, a dosage level that is in the range of from about 0.2mg. to about 2 mg. per kg. of body weight per day is most desirablyemployed in order to achieve effective results.

The following examples are given by way of illustration.

EXAMPLE I p-Nitro-N(4,4-diethoxybutyl)-benzenesulfonamidep-Nitrobenzenesulfonyl chloride (22.10 g., orv 0.10 m.) was slowly addedto a cold dimethoxyethane solution of -aminobutyraldehyde diethyl acetal(19.30 g. 0.12 In.) containing 20 g. of triethyl'amine. After thesolution'was stirred for 20 minutes, benzene was added, followed byextraction of water. After the organic layer was dried over anhydrousmagnesium sulfate, the solvent' was removed at reduced pressure. Theresidue was recrystallized 4 from a mixture of benzene and cyclohexane,MP. 58-- 60 C.

Elemental'analysis confirmed the empirical formula for C14H22N206S-EXAMPLE 'II 2-ethoxy-1-(n-nitrophenylsulfonyl)pyrrolidine p-Nitro-(4,4-diethoxybutyl) benzenesulfonamide (10.0 g.), prepared in accordancewith Example I, was dissolved in ethyl alcohol. The'solution was heatedon a steam bath, in the presence of a few drops of cone. hydrochloricacid, for 10 min. The solution was cooled and the solid was collected.The compound can be recrystallized from n-hexane, M.P. 7 02 C.

Elemental analysis confirmed the empirical formula for c 2H15N2O5S.

. EXAMPLE III p-Bromo-N- (4,4-diethoxybutyl) -benzenesulfonamide vEXAMPLE IV 1- (p-bromophenylsulfonyl -2-ethoxypyrrolidinep-Bromo-N-(4,4-diethoxybutyl) benzenesulfonamide (10 g.) of Example IIIwas dissolved in 30 ml. of ethyl alcohol and the solution heated on asteam bath for 30 min. in the presence of 8 drops of concphydrochloricacid. After the solvent was removed at reduced pressure, the residue wasrecrystallized from cyclohexane, M.P. 513 C.

Elemental analysis confirmed the empirical formula for CmHmBI'NOgS.

EXAMPLE V 2,2-ethylenedioxybis[1-(p-bromophenylsulfonyl)- pyrrolidine]p-Bromo N (4,4 diethylbutyl) benzenesulfonamide of Example III (12.0 g.or 0.0313 m.) was dissolved in ml. of ethylene glycol and heated on asteam bath, in the presence of 5 drops of hydrochloric acid, for 1 hour.The solution was let stand at room temperature overnight. The solid wascollected and washed with ethyl alcohol. 8.0 g. was obtained. Thecompound was recrystallized from benzene, M.P. 188-190 C.

Elemental analysis confirmed vthe empirical formula forC22H26BI'2N2O5S2.

7, EXAMPLE VI 1-p-aminophenylsulfonyl 2-ethoxypyrrolidine 1 The aminocompound is prepared from the corresponding l-p-nitro compound bycatalytic hydrogenation using a platinum oxide catalyst.

7 EXAMPLE VII 1- (p-bromophenylsulfonyl) -2- [2- (diethyl amino -ethy1thioJpyrrolidinehydrochloride p-B'romo-N-(4,4-diethoxybutyl)benzenesulfonamide of Example III (3.80 g. or 0.01 m.) and N,N-diethyl-'alr'ninoethanethiolj hydrochloride (2.50 gi or 0.015 m.) were dissolvedin 50 ml.'of isopropyl alcohol and-the solution heated on as'team'bath', 'in'tlie presence of '1 drop of cone. hydrochloride, for 3hours. The solution was concentrated" at reduced pressure and theresidue recrystallized from isopropyl alcohol, M.P. 127-8" C.

Elemental analysis confirmed the empirical formula forCmHnBI'NzOgSz'HCI.

EXAMPLE VIII 1- (p-bromophenylsulfonyl) -2- 1-thiazo1in-2-yl-thiopyrrolidine p-Bromo-N-(4,4-diethoxybutyl) benzenesulfonamide of ExampleIII (10.0 g. or 0.0263 in.) and Z-mercaptothiazoline (5.0 g. or 0.0425m.) were dissolved in dioxane and the solution heated on a steam bathfor 30 minutes in the presence of a few drops of concentrated HCl. Asmall amount of insoluble material was filtered off and the filtrateconcentrated. The residue was recrystallized from dioxane to give 5.10g., M.P. 1835 C.

Elemental analysis confirmed the empirical formula fOl C13H15BIN2O2S3-EXAMPLE IX pAcetamido-N-(4,4-diethoxybutyl)benzenesulfonamide EXAMPLE X4-(2-ethoxy-l-pyrrolidinylsulfonyl)-acetanilide pAcetamido-N-(4,4-diethoxybutyl) benzenesulfonamide (8.00 g. or 0.0223m.), prepared as in Example IX, was dissolved in C H OH and the solutionwas let stand at room temperature in the presence of 5 drops of conc.hydrochloric acid. The solid was collected and rinsed with ethylalcohol. This gave 4.50 g. of a solid melting at 113- 5 C.

Elemental analysis confirmed the empirical formula I01 C 4H oN O4S.

EXAMPLE XI 1- (p-chloro-o-toluenesulfonyl) -2-ethoxypyrro1idine Adimethoxyethane solution of p-chloro-o-toluenesulfonyl chloride isslowly added to a cold solution of -yaminobutyraldehyde dimethyl acetaland triethylamine in the same solvent. The mixture is stirred for 15minutes and benzene is then added. The resulting benzene solution isfirst washed with water and then dried over anhydrous magnesium sulfate.After the drying agent is removed, benzene is removed at reducedpressure. The residue is then dissolved in ethanol. After a few drops ofhydrochloric acid are added to the ethanol solution, the latter is leftto stand at room temperature overnight. Ethenol is thereafter removed atreduced pressure, and the resulting residue is recrystallized fromethanol to give 1- (p-chloro-o-toluenesulfonyl) -2-ethoxypyrrolidine.

EXAMPLE XII l-p-ethylphenylsulfonyl-2-ethylthioethylthiopyrrolidine Theabove compound is prepared by reacting N-(4,4-

diethoxybutyl)-p-ethylbenzenesulfonylamide with 2-ethylthioethylmercaptan according to the procedure of Example IV.

EXAMPLE XIII 1 l-p-bromophenylsulfonyl-2-phenylthiopyrrolidine The abovecompound is prepared by reacting p-bromo-N-(4,4-diethoxybutyl)-benzenesulfonamide with thiophe- 1101 according tothe procedure of Example IV.

' 6 EXAMPLE XIV 1-p-tolylsulfonyl-2-cyclohexyloxy-pyrrolidine The titlecompound is prepared by reacting-N-(4,4-diethoxybutyl)-p-tolylsulfonamide with cyclohexanol according tothe procedure of Example IV.

EXAMPLE XV2,2'-ethylenedithiobis-(2,4-dimethylbenzenesulfonylpyrrolidine) Theabove compound is prepared by reacting N-(4,4- diethoxybutyl) 2,4dimethylbenzenesulfonamide with ethylenedithiol according to theprocedure of Example V.

EXAMPLE XVI m-Chloro-N- 4,4-diethoxybutyl) -p-toluenesulfonamide Byfollowing the procedure of Example I and using:m-chloro-p-toluenesulfonyl chloride instead of p-nitrobenzenesulfonylchloride as starting material, the above compound is prepared.

EXAMPLE XVII 1-(m-chloro-p-toluenesulfonyl)-2-ethoxypyrrolidine Byfollowing the procedure of Example II, but substitutingm-chloro-N-(4,4-diethoxybutyl)-ptoluenesulfonamide as starting material,the above compound is prepared.

EXAMPLE XVIII m-Amino-p-chloro-N-(4,4-diethoxybutyl)benzenesulfonamideAgain following the procedure of Example I, but in this instance usingm-amino-p-chlorobenzenesulfonyl chloride as starting material, the abovecompound is prepared.

EXAMPLE XIX 1- m-amino-p-chlorophenylsulfonyl) -2-ethoxypyrrolidineUtilizing the procedure of Example II, and substitutingm-amino-p-chloro-N -(4,4 diethoxybutyl)benzenesulfonamide as startingmaterial, the above compound is prepared.

EXAMPLE XX m-Amino-p-chloro-N-(4,4-diethoxybutyl)-o-toluenesulfonamideUsing m-amino-p-chloro-o-toluenesulfonyl chloride as starting materialin the procedure of Example I, the above compound is obtained.

EXAMPLE XXI 1-(m-amino-p-chloro-o-toluenesulfonyl)-2-ethoxypyrrolidineBy following the procedure of Example II and substitutingm-amino-p-chloro-N-(4,4-diethoxybutyl)-o-toluenesulfonamide as startingmaterial, the above compound is obtained.

We claim:

1. A compound of the formula:

wherein R and R are each selected from the group consisting of hydrogen,lower alkyl, halogen, nitro and lower alkanoylamino; R and R are eachselected from the group consisting of hydrogen, lower alkyl, halogen,nitro, amino and lower alkanoylamino; R is selected v v v 8- from thegroup consisting of alkyl, nitro, amino and 9 References Cited V loweralkanoy1am1no;andZ1s I I UNITED STATES PATENTS NH(CH2)3CH(OR7)23,453,289 7/1969 'Wei et a1. 26032 6.82 wherein 7 is lower alkyL 5 HENRYJI LES, Primary Examiner 2. A compound as defined in claim 1 which is:C.', M. SHURKO, Assistant Examiner p-nitro-N- (4,4- diethoxybuty1)-benzenesulfonamide.

3. A compound as defined in claim 1' which is:

' us. c1 X.R. p-acetarnido-N-(4,4-diethoxybuty1)benzenesulfonamide. 10260-556

1. A COMPOUND OF THE FORMULA: